Related tables, figures and sidebars

A team at the Memorial Sloan-Kettering Cancer Center has shown that CXC chemokine receptor 2 antagonists sensitized tumors to chemotherapy in mouse
models of metastatic breast cancer.1 The team is working on
additional preclinical studies with the intention of moving the antagonists
into clinical trials for breast cancer.

Resistance to chemotherapy often occurs in breast cancer
as a result of a small percentage of cancer cells that develop a survival
advantage and show a more aggressive, metastatic phenotype.

The challenge has been identifying the factors that
confer the survival advantage and figuring out how to target them in
combination with chemotherapy to prevent resistance, tumor relapse and
metastasis.

Building on that work, the group set out to determine
the mechanism that linked CXC ligand expression on tumors to chemotherapeutic
resistance, with the hope of identifying molecular targets to prevent
resistance.

Massagué is chairman of the Cancer Biology and Genetics
Program and director of the Metastasis Research Center at Memorial
Sloan-Kettering. He is also a Howard Hughes Medical Institute
investigator. The team included researchers from Cancer Research UK.

The team found that CXCL1 and CXCL2 were amplified in
7.5% of human primary breast cancer tissues tested and 19.9% of metastases,
suggesting both chemokines were associated with invasiveness. In mouse
xenograft models of metastatic breast cancer, small hairpin RNA against CXCL1
and CXCL2 decreased mammary tumor growth and metastasis compared with shRNA
control.

Although the levels of CXCL1 and CXCL2 were elevated in
the breast cancer tissue, the levels of their receptors, including CXC
chemokine receptor 2 (CXCR2; IL8RB), were low. That
suggested the prosurvival effects of the ligands might be the result of their
actions on tissues surrounding the tumor.

Thus, the team set out to determine whether the ligands
were altering the activity of cells within the tumor microenvironment.

Indeed, in the same mouse models, CXCL1 and CXCL2
knockdown decreased levels of complement receptor 3 (Cr3; Cd11b)+/lymphocyte antigen 6 complex locus G
(Ly6g; Gr1)+ myeloid cells, which express
higher levels of CXCR2 than other stromal cells, in the tumor microenvironment.
Moreover, coculture of the tumor and Cd11b+/Gr1+ myeloid cells prevented the tumor
cells from undergoing chemotherapy-induced apoptosis. That suggested the Cd11b+/Gr1+ myeloid cells were mediating the
chemotherapy resistance of the tumor cells.

"The tumor-promoting effects of the tumor
microenvironment have been gaining attention, and the CXCL/CXCR2 axis seems to
be one of the key signals in the tumor microenvironment," Ijichi Hideaki
told SciBX. He is a
research associate in the Department of Gastroenterology at The University of Tokyo Hospital.

"Combination of conventional chemoreagents, which
target tumor cells directly, and modulators of the tumor microenvironment might
be a promising strategy for synergistic treatment of cancer," he added.

Next steps

Before CXCR2 antagonists can be tested
in combination with chemotherapeutics in the clinic, researchers agree that
extensive preclinical evaluation of efficacy will be required. It will also be
necessary to address a few potential adverse effects.

The Sloan-Kettering study "used mostly xenograft
models, and they did not examine CXCR2-antagonizing effects on genetically
engineered models," said Hideaki. "If they could also see consistent
results as well as prolonged overall survival using these models, it would
strengthen their findings."

Indeed, Massagué told SciBX his team's next steps include
extensive preclinical analysis with different CXCR2 inhibitors and
chemotherapeutics for different durations. "Patient-derived grafts and
transgenic models need to be tested side by side with xenografts to understand
the full gamut of efficacy of these CXCR2 inhibitors in reducing breast
metastasis," he said.

These studies are underway.

Potential side effects need to be evaluated as well,
said Hideaki.

"Since CXCR2 is known to be involved in the host
resistance to bacterial and fungal infections and the wound healing response,
antagonizing CXCR2 might cause certain disadvantages," he said. "This
should be carefully investigated in
vivo using multiple genetically engineered cancer models to
clarify not only the therapeutic effects but also certain adverse effects."

He added that humans have an additional CXCR1 and CXCR2 ligand that
mice lack, IL-8 (CXCL8), which is involved in
many aspects of different diseases. Because most in vivo functional evidence
of the CXCR2-antagonism effect was shown using mouse models, the researchers
should be careful about this difference between humans and mice, he said.

At least two CXCR2 antagonists have already been evaluated
in clinical safety studies, although according to Hideaki "no trials have
been performed in cancers."

CXCR2 antagonists in the clinic include AstraZeneca plc's AZD5069, which is in Phase II
testing to treat chronic obstructive pulmonary disease (COPD), and Dompe Farmaceutici S.p.A.'s
Reparixin, which is in Phase
II testing for graft and renal transplant rejection. The companies declined to
comment.

Markers

In addition to the potential therapeutic
applications of the findings, the team thinks the results have important
implications for breast cancer diagnosis and prognosis.

Massagué told SciBX
his team has confirmed a strong association between S100A8 and S100A9 and
resistance to perioperative chemotherapy. "This could lead to useful
markers of resistance and relapse in the future."

He added, "Since S100A8 and S100A9 are easy to
detect in serum and tissues, these markers might also be useful for developing
clinical assays in the future."

Massagué said Sloan-Kettering has filed a provisional
U.S. patent application covering the work, and the IP is available for
licensing.

Access this BioCentury Innovations article article for your individual use via a permanent link that allows you to read or print the article: $100.
The article link will be posted on the purchase transaction web page, and also emailed to you with your purchase confirmation.

Purchase This Article for Limited One-Time Distribution and Posting to Your Website :

Receive a formatted PDF reprint of this article with rights for limited one-time redistribution and posting to your website: $750. Please allow 24-48 hours for delivery.

Purchase Options

Purchase this article for individual use $100 USDPurchase this article for limited one-time distribution and website posting $750 USD